POMT2 mutations cause α-dystroglycan hypoglycosylation and Walker-Warburg syndrome

J. Van Reeuwijk, M. Janssen, C. Van Den Elzen, D. Beltran-Valero De Bernabé, P. Sabatelli, L. Merlini, M. Boon, H. Scheffer, M. Brockington, F. Muntoni, M. A. Huynen, A. Verrips, C. A. Walsh, P. G. Barth, H. G. Brunner, H. Van Bokhoven

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Abstract

Background: Walker-Warburg syndrome (WWS) is an autosomal recessive condition characterised by congenital muscular dystrophy, structural brain defects, and eye malformations. Typical brain abnormalities are hydrocephalus, lissencephaly, agenesis of the corpus callosum, fusion of the hemispheres, cerebellar hypoplasia, and neuronal overmigration, which causes a cobblestone cortex. Ocular abnormalities include cataract, microphthalmia, buphthalmos, and Peters anomaly. WWS patients show defective O-glycosylation of α-dystroglycan (α-DG), which plays a key role in bridging the cytoskeleton of muscle and CNS cells with extracellular matrix proteins, important for muscle integrity and neuronal migration. In 20% of the WWS patients, hypoglycosylation results from mutations in either the protein O-mannosyltransferase 1 (POMT1), fukutin, or fukutin related protein (FKRP) genes. The other genes for this highly heterogeneous disorder remain to be identified. Objective: To look for mutations in POMT2 as a cause of WWS, as both POMT1 and POMT2 are required to achieve protein O-mannosyltransferase activity. Methods: A candidate gene approach combined with homozygosity mapping. Results: Homozygosify was found for the POMT2 locus at 14q24.3 in four of 11 consanguineous WWS families. Homozygous POMT2 mutations were present in two of these families as well as in one patient from another cohort of six WWS families. Immunohistochemistry in muscle showed severely reduced levels of glycosylated α-DG, which is consistent with the postulated role for POMT2 in the O-mannosylation pathway. Conclusions: A fourth causative gene for WWS was uncovered. These genes account for approximately one third of the WWS cases. Several more genes are anticipated, which are likely to play a role in glycosylation of α-DG.

Original languageEnglish
Pages (from-to)907-912
Number of pages6
JournalJournal of Medical Genetics
Volume42
Issue number12
DOIs
Publication statusPublished - Dec 2005

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Walker-Warburg Syndrome
Dystroglycans
Mutation
Genes
Glycosylation
Hydrophthalmos
Eye Abnormalities
Microphthalmos
Muscles
Muscular Dystrophies
Extracellular Matrix Proteins
Brain
Hydrocephalus
Cytoskeleton
Cataract
Muscle Cells
Immunohistochemistry

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Van Reeuwijk, J., Janssen, M., Van Den Elzen, C., Beltran-Valero De Bernabé, D., Sabatelli, P., Merlini, L., ... Van Bokhoven, H. (2005). POMT2 mutations cause α-dystroglycan hypoglycosylation and Walker-Warburg syndrome. Journal of Medical Genetics, 42(12), 907-912. https://doi.org/10.1136/jmg.2005.031963

POMT2 mutations cause α-dystroglycan hypoglycosylation and Walker-Warburg syndrome. / Van Reeuwijk, J.; Janssen, M.; Van Den Elzen, C.; Beltran-Valero De Bernabé, D.; Sabatelli, P.; Merlini, L.; Boon, M.; Scheffer, H.; Brockington, M.; Muntoni, F.; Huynen, M. A.; Verrips, A.; Walsh, C. A.; Barth, P. G.; Brunner, H. G.; Van Bokhoven, H.

In: Journal of Medical Genetics, Vol. 42, No. 12, 12.2005, p. 907-912.

Research output: Contribution to journalArticle

Van Reeuwijk, J, Janssen, M, Van Den Elzen, C, Beltran-Valero De Bernabé, D, Sabatelli, P, Merlini, L, Boon, M, Scheffer, H, Brockington, M, Muntoni, F, Huynen, MA, Verrips, A, Walsh, CA, Barth, PG, Brunner, HG & Van Bokhoven, H 2005, 'POMT2 mutations cause α-dystroglycan hypoglycosylation and Walker-Warburg syndrome', Journal of Medical Genetics, vol. 42, no. 12, pp. 907-912. https://doi.org/10.1136/jmg.2005.031963
Van Reeuwijk J, Janssen M, Van Den Elzen C, Beltran-Valero De Bernabé D, Sabatelli P, Merlini L et al. POMT2 mutations cause α-dystroglycan hypoglycosylation and Walker-Warburg syndrome. Journal of Medical Genetics. 2005 Dec;42(12):907-912. https://doi.org/10.1136/jmg.2005.031963
Van Reeuwijk, J. ; Janssen, M. ; Van Den Elzen, C. ; Beltran-Valero De Bernabé, D. ; Sabatelli, P. ; Merlini, L. ; Boon, M. ; Scheffer, H. ; Brockington, M. ; Muntoni, F. ; Huynen, M. A. ; Verrips, A. ; Walsh, C. A. ; Barth, P. G. ; Brunner, H. G. ; Van Bokhoven, H. / POMT2 mutations cause α-dystroglycan hypoglycosylation and Walker-Warburg syndrome. In: Journal of Medical Genetics. 2005 ; Vol. 42, No. 12. pp. 907-912.
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abstract = "Background: Walker-Warburg syndrome (WWS) is an autosomal recessive condition characterised by congenital muscular dystrophy, structural brain defects, and eye malformations. Typical brain abnormalities are hydrocephalus, lissencephaly, agenesis of the corpus callosum, fusion of the hemispheres, cerebellar hypoplasia, and neuronal overmigration, which causes a cobblestone cortex. Ocular abnormalities include cataract, microphthalmia, buphthalmos, and Peters anomaly. WWS patients show defective O-glycosylation of α-dystroglycan (α-DG), which plays a key role in bridging the cytoskeleton of muscle and CNS cells with extracellular matrix proteins, important for muscle integrity and neuronal migration. In 20{\%} of the WWS patients, hypoglycosylation results from mutations in either the protein O-mannosyltransferase 1 (POMT1), fukutin, or fukutin related protein (FKRP) genes. The other genes for this highly heterogeneous disorder remain to be identified. Objective: To look for mutations in POMT2 as a cause of WWS, as both POMT1 and POMT2 are required to achieve protein O-mannosyltransferase activity. Methods: A candidate gene approach combined with homozygosity mapping. Results: Homozygosify was found for the POMT2 locus at 14q24.3 in four of 11 consanguineous WWS families. Homozygous POMT2 mutations were present in two of these families as well as in one patient from another cohort of six WWS families. Immunohistochemistry in muscle showed severely reduced levels of glycosylated α-DG, which is consistent with the postulated role for POMT2 in the O-mannosylation pathway. Conclusions: A fourth causative gene for WWS was uncovered. These genes account for approximately one third of the WWS cases. Several more genes are anticipated, which are likely to play a role in glycosylation of α-DG.",
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AU - Van Reeuwijk, J.

AU - Janssen, M.

AU - Van Den Elzen, C.

AU - Beltran-Valero De Bernabé, D.

AU - Sabatelli, P.

AU - Merlini, L.

AU - Boon, M.

AU - Scheffer, H.

AU - Brockington, M.

AU - Muntoni, F.

AU - Huynen, M. A.

AU - Verrips, A.

AU - Walsh, C. A.

AU - Barth, P. G.

AU - Brunner, H. G.

AU - Van Bokhoven, H.

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N2 - Background: Walker-Warburg syndrome (WWS) is an autosomal recessive condition characterised by congenital muscular dystrophy, structural brain defects, and eye malformations. Typical brain abnormalities are hydrocephalus, lissencephaly, agenesis of the corpus callosum, fusion of the hemispheres, cerebellar hypoplasia, and neuronal overmigration, which causes a cobblestone cortex. Ocular abnormalities include cataract, microphthalmia, buphthalmos, and Peters anomaly. WWS patients show defective O-glycosylation of α-dystroglycan (α-DG), which plays a key role in bridging the cytoskeleton of muscle and CNS cells with extracellular matrix proteins, important for muscle integrity and neuronal migration. In 20% of the WWS patients, hypoglycosylation results from mutations in either the protein O-mannosyltransferase 1 (POMT1), fukutin, or fukutin related protein (FKRP) genes. The other genes for this highly heterogeneous disorder remain to be identified. Objective: To look for mutations in POMT2 as a cause of WWS, as both POMT1 and POMT2 are required to achieve protein O-mannosyltransferase activity. Methods: A candidate gene approach combined with homozygosity mapping. Results: Homozygosify was found for the POMT2 locus at 14q24.3 in four of 11 consanguineous WWS families. Homozygous POMT2 mutations were present in two of these families as well as in one patient from another cohort of six WWS families. Immunohistochemistry in muscle showed severely reduced levels of glycosylated α-DG, which is consistent with the postulated role for POMT2 in the O-mannosylation pathway. Conclusions: A fourth causative gene for WWS was uncovered. These genes account for approximately one third of the WWS cases. Several more genes are anticipated, which are likely to play a role in glycosylation of α-DG.

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